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Effects of Tiaprofenic Acid (Surgam) on Cartilage

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Effects of Tiaprofenic Acid (Surgam) on Cartilage 448 Annals ofthe Rheumatic Diseases 1992; 51: 448-455 Effects of tiaprofenic acid (Surgam) on cartilage proteoglycans in the rabbit joint immobilisation Ann Rheum Dis: first published as 10.1136/ard.51.4.448 on 1 April 1992. Downloaded from model Isabelle Meyer-Carrive, Peter Ghosh Abstract pressive deformation.4 5 Biochemical and histo- A well established model of arthritis induced chemical studies of cartilage from osteoarthritic in rabbit knee joints by immobilisation in full joints have shown that proteoglycans are lost extension for 30 days was used to evaluate the from the matrix in the more advanced stages of in vivo effects of 2-5, 5-0, and 10-0 mg/kg body the disease."8 The depletion of these macro- weight oftiaprofenic acid on articular cartilage molecules results in a decline in the resilience of proteoglycans. The drug was given sub- the tissue, and the mechanical stresses trans- cutaneously every 24 hours during the entire mitted across the joint may contribute to the immobilisation period. Immobilised animals progression of pathological changes in cartilage not treated with drugs and normal animals and subchondral bone. were used as controls. In the non-drug treated Non-steroidal anti-inflammatory drugs immobilised animals articular cartilage showed (NSAIDs) are extensively used in the manage- evidence of surface damage accompanied ment of osteoarthritis, but there is continuing by synovial hypertrophy and effusion. Proteo- debate about their beneficial or adverse effects glycan concentrations were reduced in on cartilage integrity."' Some laboratory and cartilages of these joints and the incorporation clinical evidence9 11-14 suggests that several of of 35SO24 into macromolecular proteoglycans the older NSAIDs may suppress the biosynthesis was higher than in cartilages of non-im- of proteoglycans in cartilage, thereby accel- mobilised controls. Gel filtration chroma- erating its failure rate. On the other hand, other tographic studies of both resident and 35S data indicate that the effect of certain NSAIDs labelled proteoglycans isolated from im- on cartilage is innocuous at therapeutically used mobilised joint cartilage showed reduced concentrations,'5 16 or that these drugs may aggregation and the presence of degraded even provide a protective role by support- proteoglycan subunit species. Whereas the ing macromolecule biosynthesis within joint administration of 10,0 mg/kg tiaprofenic acid tissues.'5 17 These latter studies have generally every 24 hours to immobilised animals focused on diclofenac, piroxicam, and tiapro- http://ard.bmj.com/ exacerbated the degradation and loss of fenic acid and, for the most part, have been proteoglycans from joint cartilages, 5-0 mg/kg confined to in vitro investigation. tiaprofenic acid provided some protection of In this study we considered the in vivo these macromolecules, as shown by the con- effects of various doses of tiaprofenic acid on centrations and extractability ofproteoglycans cartilage proteoglycans in a rabbit experimental from cartilages, which were comparable with osteoarthritis. The results obtained indicated, those from non-immobilised controls. A in this model at least, that the loss or preservation on September 27, 2021 by guest. Protected copyright. high incorporation of 35S into proteoglycans of proteoglycans in articular cartilage is was demonstrated, together with reduced dependent on the amount of drug given. catabolism of proteoglycans, indicating pre- servation of chondrocyte anabolic activity. At a tiaprofenic acid dose of 2.5 mg/kg, however, Materials and methods no beneficial effects on cartilage proteoglycans COMPOUNDS could be shown. Carrier free H235SO4 (specific activity 1-6 TBq/mg) was obtained from Du Pont Medical Products (Wilmington, DE, USA). Guanidine hydrochloride (grade 1), trizma base (reagent Although the cause of osteoarthritis is presently grade (TRIS)), bovine serum albumin, phenyl- unknown, there is general agreement`3 that methylsulphonyl fluoride, benzamidine hydro- failure of articular cartilage represents an early chloride, L-hydroxyproline, L-cysteine free and critical step in the progression of this base, D-glucuronolactone and hyaluronic acid disorder. Articular consists (grade 1, from human umbilical cord), whale Raymond Purves cartilage essentially Research Laboratories, of chondrocytes embedded in a hydrated gel of and shark chondroitin-4-sulphate and chon- (University of Sydney), proteoglycans which are constrained by an droitin-6-sulphate, Coomassie brilliant blue G, Royal North Shore integrated network of collagen fibrils. The and calf thymus DNA were purchased from Hospital of Sydney, St Leonards, NSW 2065, macromolecular organisation of the cartilage Sigma Chemical (St Louis, MO, USA). N- Australia extracellular matrix is complex and is still Ethylmaleimide was obtained from Calbiochem- I Meyer-Carrive the subject of investigation, but it has been Behring Australia (Sydney, Australia), papain P Ghosh established that the entrapment of the hydro- (papainase [EC 3.4.22.2] (puriss) from Fluka Correspondence to: philic proteoglycans within the collagen AG (Buchs, Switzerland), and Sepharose CL- Professor Ghosh. 2B was Pharmacia Accepted for publication meshwork confers to cartilage its hydroelastic supplied by (South Seas) 18 June 1991 properties and ability to recover from com- (Sydney, Australia). All other chemicals and Effects oftiaprofenic acid on cartilage proteoglycans 449 reagents were analytical grade or the highest Group 6: the immobilised joints of six rabbits grade available, unless specified. that received 5 mg/kg tiaprofenic acid sub- cutaneously every 24 hours during the im- Ann Rheum Dis: first published as 10.1136/ard.51.4.448 on 1 April 1992. Downloaded from mobilisation period (5 0 mg treated group). PROCEDURES Group 7: the contralateral joints of the six Induction of cartilage degeneration in the rabbit group 6 animals. knee joint by immobilisation Group 8: the immobilised joints of three The experimental series comprised 31 mature rabbits given 2-5 mg/kg tiaprofenic acid sub- (9-12 months old) New Zealand white rabbits. cutaneously during the immobilisation period Rabbit joints were immobilised by a modifica- (2-5 mg treated group). tion of published techniques.8 19 Briefly, two Group 9: the contralateral joints of the three plastic concave splints (220x25x2 mm; 200x group 8 animals. 20x2 mm) were used. The larger splint was applied to the ventral aspect of the left leg of the rabbits from the thigh to the distal end of the DISSECTION AND ANALYSIS OF TISSUES limb, which was maintained in full extension. Rabbit joints were opened and the articular The splint was attached to the limb by wrapping cartilage was removed from femoral condyles, five turns of leucoplast bandage (Johnson and suprapatellar groove, and tibial plateaux with a Johnson, Sydney, Australia) around the splint surgical blade. The cartilage from each of these and leg. The second splint was similarly fixed regions was pooled, finely diced, transferred to but to the dorsal aspect of the limb. The tension preweighed stoppered tubes, and lyophilised. in the bandage did not impair the blood supply Aliquots of the pooled anhydrous cartilage were to the leg. This procedure allowed ± 5° of analysed for hexuronic acid content, after movement of the joint within the splint. The papain digestion20 by the method of Blumen- rabbits were allowed to move freely during the krantz and Asboe-Hansen,21 using glucurono- immobilisation period, checked daily, and the lactone as a standard. The sulphated glyco- bandage replaced if damaged. saminoglycans of column fractions were measured by the methods of Farndale et a122 Drug administration and isotopic labelling of with chondroitin-6-sulphate as a standard. The articular cartilage proteoglycans radioactivity of proteoglycan samples, or The rabbits were treated prophylactically with column fractions, was determined by liquid 10-0, 5-0, or 2-5 mg/kg tiaprofenic acid during scintillation spectrometry. All analyses were the entire immobilisation period. The drug as conducted in triplicate. the trometamol salt injectable form (Roussel UCLAF, Sydney, Australia) was given sub- cutaneously every 24 hours over the 30 day EXTRACTION AND PURIFICATION OF immobilisation period, so that each animal PROTEOGLYCANS received a total of 29 injections. Twenty four Proteoglycans were dissociatively extracted http://ard.bmj.com/ hours before they were killed the drug treated from aliquots of diced wet articular cartilage immobilised group, the immobilised group not with 10 volumes of freshly prepared buffered treated with drugs, and the non-immobilised 4 M guanidine hydrochloride containing the control group not treated with drugs were protease inhibitors 25 mM EDTA, 10 mM N- injected intravenously with H235SO4 in physio- ethylmaleimide, and 1 mM benzamidine HC1 in logical saline (1-0 ml) (92-5 MBq/kg) through 50 mM TRIS at pH 7*4 for 48 hours at 4°C, as the marginal ear vein. The animals were killed described by Oegema etal.23 After centrifugation on September 27, 2021 by guest. Protected copyright. by an intravenous injection of sodium pento- (20 minutes at 2000 g) the residues were washed barbitone (75 mg/kg) into the marginal ear vein. twice with a small volume (-0 5 ml) ofextraction buffer, and the supernatants and washings were pooled. The residues were washed thoroughly EXPERIMENTAL GROUPS EXAMINED (48 hours extraction) with distilled water and The following groups were examined: lyophilised before papain digestion.20
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